Despite a wealth of data indicating that morphine can modulate the immune system indirectly by acting in the brain, little is known regarding the neural mechanisms that underlie opioid-induced immunomodulation. The current proposal seeks to further establish and extend our recent finding that central dopamine systems mediate the effects of morphine on the immune system. In particular, this proposal seeks to elucidate the role of nucleus accumbens dopamine in opioid-mediated neuroimmune regulation. Specific Aim I tests the hypothesis that morphine-induced reductions in splenic NK cell activity occur via activation of dopaminergic neurons that project to the nucleus accumbens. Specific Aim II elaborates upon the first aim by testing specific dopamine receptor mechanisms that mediate morphine-induced NK cell suppression. Specific Aim directly and thoroughly tests the hypothesis that activation of opioid receptors in the VTA mediates morphine's suppressive effect on NK cell activity by stimulating dopaminergic neurons innervating the nucleus accumbens. Collectively, the proposed studies will provide innovative and important new data regarding the neural mechanisms underlying immunomodulation by opioid drugs.